The present invention relates to a polystyrene sulfonate-containing preparation which can be easily taken with a drastically reduced intake of water for ingestion, and particularly to a gel therapeutic agent for hyperpotassemia, which comprises polystyrene sulfonate as an active ingredient.
Conventional therapies applied to patients with hyperpotassemia include calcium gluconate therapy, glucose-insulin therapy, sodium bicarbonate therapy, saline therapy or a combination thereof for relative emergency cases, or dialysis therapy and cation-exchange therapy based on administration of cation-exchange resin such as polystyrene sulfonate for non-emergency cases. Among these therapies, the cation-exchange therapy involving removing potassium from the body by replacement of potassium ions in intestinal tracts is generally conducted for patients with chronic renal insufficiency, and in this therapy, a daily dosage of 15 to 30 g polystyrene sulfonate for an adult person is divided into 2 to 3 portions and each portion is suspended in 30 to 50 ml water and orally administered. However, polystyrene sulfonate is a powder which is hardly dissolved in water and it should be taken in a large amount, so it feels strongly unpleasant in the oral cavity upon ingestion, and it is noted that there are many cases where compliance with clinician""s instructions is not obeyed.
The polystyrene sulfonate when suspended in water is easily precipitated at the bottom of a cup, thus making it difficult to take the whole dose all at once, so some patients take powdery sulfonate polystyrene with water in the oral cavity without previously suspending it. In this case, there is a possibility that the polystyrene sulfonate is not uniformly dispersed in digestive tracts and forms agglomerates, thus failing to bring about the desired pharmaceutical effect. Further, the polystyrene sulfonate when taken in the form of powder feels strongly unpleasant in the oral cavity, to become a great mental burden on the patient. Hence, the polystyrene sulfonate gives a remarkably unpleasant feeling in the oral cavity, and according to the present application method, it is difficult to take the whole of a prescribed dose all at once, so under the present circumstances, the patient drinks a large amount of water to take it, which is contraindicated for renal insufficiency.
Recently, the method of administering the pharmaceutical preparation is recently devised in some hospitals, and it is reported that the improvement of compliance is attempted by manufacturing calcium polystyrene sulfonate etc. into jelly preparations {xe2x80x9cShinryo To Shinyakuxe2x80x9d, Vol. 29, No. 2, p. 514 (1992), xe2x80x9cShinryo To Shinyakuxe2x80x9d, Vol. 31, No. 11, p. 1911 (1994); and xe2x80x9cIyaku No Monxe2x80x9d, Vol. 31, No. 3, p. 190 (1991)}.
However, even in the above-described polystyrene sulfonate-containing jelly preparations, there remain the following problems:
(a) The polystyrene sulfonate-containing jelly preparations reported in the above literatures feel rough like sand, and are inferior in a sense of ingestion. This sense of roughness remains considerably in the oral cavity, and especially 50% or more polystyrene sulfonate is precipitated at the bottom of a vessel at the time of manufacturing the jelly preparation, and thus a sense of significant roughness is felt upon ingestion of the jelly preparation sedimented at the bottom of the vessel, and the removal of this unpleasant sense or sense of foreign matter requires drinking water, which results in an excessive intake of water to cause a great problem for patients with renal insufficiency.
(b) While the variability of contents in jelly confectionery as general food is acceptable at certain degrees, the amounts of contents in the jelly preparation as a pharmaceutical preparation should be strictly guaranteed. However, the majority of polystyrene sulfonate is precipitated upon introduction into a solution before gelation, so it is difficult to set a predetermined content of said salt in the jelly preparation, and accordingly it is almost impossible to produce a large amount of a jelly preparation with a constant content of said salt. To prepare a large amount of a jelly preparation with a constant content of polystyrene sulfonate, it is conceivable that a predetermined amount of said salt is introduced into each vessel and then a solution for gelation is poured into it. However, the polystyrene sulfonate in the vessel is poor in uniform dispersibility, and thus upon ingestion of a part containing a large content of said salt, those who take it feel significantly unpleasant in the oral cavity. Therefore, manual manufacturing of the jelly preparation, such as dispensing it little by little rapidly with stirring, is necessary under the present circumstances, but this makes the operation complicated and productivity lowered. After all, it is very difficult or impossible to prevent the polystyrene sulfonate from being unevenly distributed in the jelly preparation.
(c) The amount of water in the conventional polystyrene sulfonate-containing jelly preparation is at least 100 ml/preparation, and accordingly if it is administered 3 times every day, the intake of water will be at least 300 ml/day. Further, if water is taken in an amount of 50 ml for each administration to relieve the significant unpleasant feeling, the amount of water taken for the administration is further increased to be more than 450 ml/day. However, the daily intake of water for a patient with renal insufficiency is limited to 400-700 ml in order to relieve the burden on the kidney. Accordingly, if the polystyrene sulfonate-containing jelly preparation is administered, the amount of water (including drinking water) which can be taken from other materials than said preparation is made less than half of the usual amount or is very small in some cases, thus significantly impairing the life or quality of life (QOL) of the patient and bringing about a mental burden on the patient.
An object of the present invention is to solve the above-described prior art problems all at once. That is, the problem to be solved by the invention is to provide polystyrene sulfonate-containing gel preparations with a reduced content of water and with a reduced unpleasant feeling at the time of administration or ingestion, whereby the amount of water taken for administration, as a great problem in patients with renal insufficiency, can be reduced. A further object is to guarantee the content of polystyrene sulfonate in a pharmaceutical preparation and to enable production thereof in a large amount at the industrial level.
The polystyrene sulfonate-containing gel preparation according to the present invention is characterized in that the particle diameter of polyethylene sulfonate is made uniform within the range of at least 5-100xcexcm. Further, it is characterized in that the viscosity before gelation is adjusted depending on its particle size by adding a thickening agent and the polystyrene sulfonate particles after gelation are uniformly dispersed. More preferably, it is characterized in that a part of contained water is replaced by containing a water-displacing agent.
Hereinafter, the gel preparation of the present invention is described in more detail.
At the time of preparing the polystyrene sulfonate-containing gel preparation of the present invention, adjustment of the viscosity of its solution before gelation is conducted so that a prescribed amount of the active ingredient is contained in an uniformly dispersed state in the preparation without deteriorating the ability of said salt on ion exchange, and simultaneously the unpleasant sense of roughness in the oral cavity upon administration is reduced. As a result of reduction of the unpleasant sense of roughness in the oral cavity, the patient can reduce water intake for ingestion of said preparation.
The viscosity of the solution at 50xc2x0 C. before gelation is adjusted by the thickening agent specifically to 50 cP or more in case where the particle diameter of polystyrene sulfonate is 5-25 xcexcm, to 100 cP or more in case of 5-50 xcexcm, to 300 cP or more in case of 5-75xcexcm, and to 1000 cP or more in case of 5-100 xcexcm. The present inventors have found that if dispensed into each vessel after this adjustment of viscosity, a gel preparation containing a prescribed amount of the salt in a uniformly dispersed state can be obtained without precipitating polystyrene sulfonate particles (see Test Example 1 below) and further that the unpleasant sense of roughness in the oral cavity upon ingestion of said preparation is reduced.
Strictly speaking, if polystyrene sulfonate with a particle size of 5 to X xcexcm is used to prepare the gel preparation, the viscosity of its solution is adjusted to that viscosity read from FIG. 2 in the appended drawings at which particles having a particle diameter of X xcexcm are not precipitated, whereby the desired preparation can be obtained.
The above-mentioned viscosity of 50 cP is not a lower limit, and the viscosity has a further lower value if the majority of particles have a diameter of e.g. 5-10 xcexcm, and for example, the viscosity before gelation can be adjusted to 50 cP or so by incorporating a small amount of large particles (e.g. 100 xcexcm) into particles having a diameter of 20-35 xcexcm.
This adjustment of viscosity can be conducted by using at least one substance of various thickening agents, sugars and sugar alcohols. In this case, the thickening agent is not particularly limited, and mention can be made of natural polysaccharides such as xanthan gum and guar gum, water-soluble derivatives of cellulose, such as hydroxypropyl cellulose and carboxymethyl cellulose, starch derivatives such as carboxymethyl starch, alginic acid derivatives such as alginic acid polypropylene glycol ester, and polyacrylic acid derivatives. Further the sugars and sugar alcohols are not particularly limited, and mention can be made of various sugars such as glucose, xylose, maltose, sucrose, lactose, dextrin, invert sugars, and starch hydrolysate, and sugar alcohols such as sorbitol, mannitol, xylitol, maltitol and hydrogenated malt starch hydrolysate. In the present specification, all the thickening agents, sugars and sugar alcohols are collectively referred to as thickening agent, as a matter of convenience.
The gel preparation of the present invention is defined based on the adjustment of the viscosity of the solution before solidification but not of the final preparation, as described above, and this is because it is very difficult or impossible to define it in the state of the final preparation, and the gel preparation is defined specifically in terms of the viscosity of its solution at a temperature of 50xc2x0 C.; this is because this temperature is a general dispensing temperature when a gel preparation is prepared.
The reason for controlling the particle diameter of polystyrene sulfonate in the present invention within the range of at least 5-100 xcexcm is for further reducing the unpleasant sense of roughness in the oral cavity upon ingestion. That is, the present inventors have noticed that the sense of ingestion is not sufficiently improved by merely attempt to uniformly disperse polystyrene sulfonate with the above thickening agent, and after repeated trial and error, the present inventors have found that the sense of roughness in the oral cavity is significantly relieved by controlling the particle diameter of said salt, that is, by making the particles small. Then, the present inventors concluded that if the particle diameter is made 100 xcexcm or less, the gel or jelly preparation can be administered as such without drinking water (see Test Example 2 below). Accordingly, the diameter is preferably smaller within this range. The diameter is preferably 5 to 75 xcexcm, more preferably 5 to 50 xcexcm, and most preferably 5 to 25 xcexcm.
The polystyrene sulfonate used in the present invention is not particularly limited insofar as it is a pharmaceutically acceptable salt, and its calcium salt and sodium salt can be mentioned. In the commercial polystyrene sulfonate powder for pharmaceutical preparations, the content of 5 xcexcm or less fine particles is regulated to 0.1% or less in order to prevent the particles from being precipitated on tissues in a reticuloendothelial system after absorption via mucosa, but particles of a relatively large size of 100 to 200 xcexcm account for 20% or more of the whole. The particles of a desired size can be easily obtained from the commercial polystyrene sulfonate powder for pharmaceutical preparations by a general method, that is, by sieving or with a grinding classifying machine.
A water-displacing agent is not necessarily required to be contained in the gel preparation of the present invention, but nevertheless it is preferably contained. This is to substitute for a part of water in the gel preparation, whereby the water content in the gel preparation can be minimized without reducing the gel volume. The intake of water, accompanying ingestion of said preparation, can be minimized without deterioration of a sense of ingestion.
The water-displacing agent is not particularly limited, and it is possible to use at least one substance of glycerin, propylene glycol, polyethylene glycols, sugars and sugar alcohols. The sugars include glucose, xylose, maltose, sucrose, lactose, dextrin, invert sugars and starch hydrolysates, and sugar alcohols include sorbitol, mannitol, xylitol, maltitol, and hydrogenated malt starch hydrolysate. These may overlap with the above thickening agent.
The water-displacing agent is not essential because in the present invention, the amount of water can be simply reduced in order to decrease the water content in the gel preparation. If the amount of water used is reduced in the conventional polystyrene sulfonate-containing gel preparation, the gel (jelly) volume is also reduced as shown in Test Example 6, and simultaneously a sense of ingestion is significantly worsened thus making it inevitable to drink further water after all, so the amount of water used could not be simply reduced. That is, reduction of the amount of water used (reduction of the gel volume) was incompatible with improvement of the sense of ingestion. However, it was revealed that in the polystyrene sulfonate-containing gel preparation of the present invention, even if the amount of water used is reduced in order to decrease the gel volume, the sense of ingestion is worsened only slightly as a result of significant improvement of the sense of ingestion by uniform dispersion with the above thickening agent and by regulating the particle diameter to 5-100 xcexcm (see Test Examples 4 and 6 below). This means that the present invention achieves reduction of the amount of water used (reduction of the gel volume) and simultaneous improvement of the sense of ingestion, so that even if there is no water-displacing agent, sufficient reduction of the water content and improvement of the sense of ingestion can be achieved, as compared with the conventional products.
The amount of water contained in the gel preparation disclosed as the present invention is 60 ml or less every 5 g polystyrene sulfonate or 12 ml per every 1 g thereof, and water is contained preferably in a less amount in the range where the uniform dispersion of polystyrene sulfonate and improvement of the sense of ingestion are achieved. For easy handling of the product, it is considered most preferable that a single dose of 5 g polystyrene sulfonate has a gel volume of about 20 to 30 ml, and the amount of water contained in this case is smaller than said gel volume, that is, about 12 to 20 ml is considered most preferable. If the amount of water is further reduced, it is possible that the ingredients contained are hardly dissolved or the polystyrene sulfonate cannot be uniformly dispersed.
The gelling agent for preparing the gel preparation of the present invention is not particularly limited, and mention can be made of agar, carrageenan, locust bean gum, alginic acid and salts thereof, gelatin, pectin, carboxymethylcellulose, and starch.
The gel preparation of the present invention can be prepared in accordance with a conventional method of preparing jelly confectionery, that is, by dissolving various components by heating, dispensing the solution into a suitable vessel, and cooling it. The appearance is in the form of solid such as jelly, pudding, Bavarian cream and gummi to the form of starch paste, and it can be dispensed in a cup, bag, tube etc. and packaged. Further, additives such as pH adjuster, flavor, coloring matter, sweetener and antimicrobial agent can be contained, if necessary.
Hereinbefore, the gel preparation of the present invention has been described. By combination of the means described above, the water content in the polystyrene sulfonate-containing gel preparation of the present invention was significantly reduced. The water content in the gel preparation of the present invention described in the Production Examples is 15 to 60 ml per every 5 g polystyrene sulfonate, and the water content can be reduced to 15 to 60% of the conventional gel preparations containing said salt (100 ml per every 5 g polystyrene sulfonate). Further, there is little need for drinking water for ingestion of said preparation, and as shown in Test Example 3, the total intake of water is xc2xc to ⅕ as compared with that of the conventional preparation, and 300 to 400 ml of water intake daily could be reduced. A daily amount of water intake is limited to 400 to 700 ml for patients with renal insufficiency, but 400 ml or more water is taken in total when the conventional polystyrene sulfonate preparation is ingested, thus leading to consumption of xc2xd or more of the limited amount of water or even the total amount in some cases. As a result, there arises a need for significant reduction of the amount of water taken from other materials (food and drinking water) than said preparation, resulting in significant deterioration of xe2x80x9cquality of lifexe2x80x9d of the patient. In consideration of these, it is understood that the effect of reducing the water intake by 300-400 ml/day according to the invented preparation is extremely significant. As a result, it is possible to control patient""s water intake strictly and to further improve xe2x80x9cquality of lifexe2x80x9d of the patient significantly.
The preparation of the present invention having an average water content is used in Test Example 3, but if the preparation of the present invention having a less water content is used as shown in Production Example 10 or 13, the daily amount of water taken when said preparation is ingested is reduced to about 50 ml, to make its effect more significant.
In the polystyrene sulfonate-containing gel preparation as a pharmaceutical preparation, the content of said salt as the active ingredient should be strictly guaranteed. In the conventional preparation, the content of the polystyrene sulfonate as the active ingredient or its effective amount for administration have not been guaranteed as described above. In the polystyrene sulfonate-containing gel preparation of the present invention, the polystyrene sulfonate as the active ingredient is strictly guaranteed as an effective amount, as described above, and a polystyrene sulfonate preparation conforming to standards as a pharmaceutical preparation can be produced for the first time at the industrial level.